Use of therapeutic oligonucleotides, including double-stranded RNA (dsRNA), in the clinic has been hampered by the lack of efficient and safe delivery systems. Cationic lipids have been used to deliver therapeutic oligonucleotides, however, their use is limited by cell toxicity and the fact that cationic lipids accumulate primarily in the liver.
International Patent Publication Nos. WO 2008/104978, WO 2009/044392, WO 2011/066475, WO 2011/084193 and WO 2011/085056 disclose chemically modified dsRNA, and are hereby incorporated by reference in their entirety.
A process for large-scale preparation of sphingosine is provided in U.S. Pat. No. 6,469,148 and sphingolipid-polyalkylamine conjugates are disclosed in U.S. Pat. No. 7,771,711; both are incorporated by reference in their entirety.
PCT publication No. WO 2010/150004 relates to oligonucleotides carrying lipid molecules and their use as inhibitors of gene expression.
There remains a need for active and safe dsRNA therapeutic agents, which exhibit at least one of improved cellular uptake with enhanced endosomal release, increased circulation time, favorable biodistribution, reduced toxicity and reduced immunogenicity compared to the unmodified counterparts, while retaining therapeutic activity.